Process for reductive dehalogenation

ABSTRACT

A method of producing 2-fluorocyclopropane-1-carboxylic acid ester, which comprise by allowing a compound represented by the following formula (1): 
                         
wherein X represents a chlorine atom, a bromine atom or an iodine atom; and R 1  represents an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an aralkyl group composed of an aryl group having 6 to 12 carbon atoms and an alkylene group having 1 to 6 carbon atoms; to react with a reducing agent in the presence of a phase transfer catalyst.
 
     According to the production method of the present invention, the reaction time of dehalogenation can be greatly shortened.

TECHNICAL FIELD

The present invention relates to a method of producingfluorocyclopropane useful for producing an excellent compound forpharmaceutical agents or agricultural chemicals.

BACKGROUND ART

Within the synthetic new quinolone antibacterial agents, quinolonederivatives containing a 1,2-cis-2-fluorocyclopropyl group as asubstituent at the 1-position have a strong antibacterial activity andare highly safe at the same time, and thus expected to be an excellentsynthetic antibacterial agent. To prepare such1,2-cis-2-fluorocyclopropyl group,1,2-cis-2-fluorocyclopropane-1-carboxylic acid is useful. This compoundis produced by dechlorinating 1-chloro-2-fluorocyclopropane-1-carboxylicacid ester in dimethyl sulfoxide in the presence of sodium borohydride(Japanese Patent Application Laid-Open No. 6-157418). However, thisdechlorination reaction has a problem that when a stirring blade is usedin the stirring step with the view of industrial production, it takesseveral days to complete the reaction, and therefore establishment of aconvenient production method with a reduced reaction time has beendesired. In addition, since dimethyl sulfoxide generates dimethylsulfide which is responsible for foul odor during the reaction, therehas been a problem of harmful effects on the environment.

Under such circumstances, an object of the present invention is toprovide a method of producing 2-fluorocyclopropane-1-carboxylic acidester by efficiently dehalogenating1-halogeno-2-fluorocyclopropane-1-carboxylic acid ester, which method isalso applicable to apparatuses for industrial production.

DISCLOSURE OF THE INVENTION

The inventors of the present invention have conducted intensive studieson dehalogenation reaction of1-halogeno-2-fluorocyclopropane-1-carboxylic acid ester, and found amethod of producing 2-fluorocyclopropane-1-carboxylic acid ester whichcomprises allowing 1-halogeno-2-fluorocyclopropane-1-carboxylic acidester to react with a reducing agent in a two-phase system in thepresence of a phase transfer catalyst, which method is also applicableto industrial scale production, and has completed the present invention.

Accordingly, the present invention provides a method of producing2-fluorocyclopropane-1-carboxylic acid ester (2), characterized byallowing a compound represented by the following formula (1):

wherein X represents a chlorine atom, a bromine atom or an iodine atom;and R¹ represents an alkyl group having 1 to 8 carbon atoms, an arylgroup having 6 to 12 carbon atoms, an alkenyl group having 2 to 8 carbonatoms, or an aralkyl group composed of an aryl group having 6 to 12carbon atoms and an alkylene group having 1 to 6 carbon atoms; to reactwith a reducing agent in the presence of a phase transfer catalyst. Theuse of the phase transfer catalyst enables an efficient two-phasereaction to proceed between an organic phase containing1-halogeno-2-fluorocyclopropane-1-carboxylic acid ester and an aqueousphase containing a reducing agent.

BEST MODE FOR CARRYING OUT THE INVENTION

In the formula (1), X represents a chlorine atom, a bromine atom or aniodine atom, with a chlorine atom being preferred.

R¹ represents an alkyl group having 1 to 8 carbon atoms, an aryl grouphaving 6 to 12 carbon atoms, an alkenyl group having 2 to 8 carbonatoms, or an aralkyl group composed of an aryl group having 6 to 12carbon atoms and an alkylene group having 1 to 6 carbon atoms. Examplesof the alkyl group having 1 to 8 carbon atoms include a methyl group, anethyl group, a propyl group, an isopropyl group, a butyl group, asec-butyl group, a t-butyl group, a pentyl group, a cyclopropyl group, acyclobutyl group and a cyclopentyl group. Examples of the aryl grouphaving 6 to 12 carbon atoms include a phenyl group and a naphthyl group.The aryl group may be further substituted by an alkyl group having 1 to6 carbon atoms such as a methyl group, an ethyl group, a propyl group,an isopropyl group, a butyl group, a sec-butyl group or a t-butyl group,an alkoxy group having 1 to 6 carbon atoms such as a methoxy group, anethoxy group or a propoxy group, a cyano group, a nitro group, a halogenatom, an amino group, a hydroxy group, a carboxy group or the like.Examples of the alkenyl group having 2 to 8 carbon atoms include a vinylgroup and a 1-isopropenyl group. Examples of the aralkyl group composedof anaryl group having 6 to 12 carbon atoms and an alkylene group having1 to 6 carbon atoms include a benzyl group and a phenethyl group. Thearyl group constituting the aralkyl group may be further substituted bythe above-mentioned alkyl group having 1 to 6 carbon atoms, theabove-mentioned alkoxy group having 1 to 6 carbon atoms, a cyano group,a nitro group, a halogen atom, an amino group, a hydroxy group, acarboxy group or the like.

As R¹, an alkyl group having 1 to 8 carbon atoms is preferable, and amethyl group, an ethyl group, a butyl group, a sec-butyl group and at-butyl group are more preferable, and a t-butyl group is even morepreferable. When R¹ is a t-butyl group, an effect of preventinggeneration of a by-product (1-chloro-2-fluoro-1-hydroxymethylcyclopropane) can be observed.

The compound (1) can be easily synthesized from1-chloro-cyclopropane-1,2-dicarboxylic acid-1-t-butyl ester according toa method described, for example, in Japanese Patent ApplicationLaid-Open No. 5-301827.

As a reducing agent used in the producing method of the presentinvention, a compound represented by the following formula (3)MBH_(m)R² _(n)  (3)can be used, wherein M represents an alkali metal atom such as lithium,sodium or potassium, and R² represents a hydrogen atom, a cyano group,an alkoxy group or an acyloxy group. As the alkoxy group, theaforementioned alkoxy groups having 1 to 6 carbon atoms are preferable.Examples of the acyloxy group include an alkylcarbonyloxy group, anarylcarbonyloxy group and an aralkylcarbonyloxy group. These alkoxygroups or acyloxy groups may be further substituted by a halogen atom orthe like. Specific examples of the alkoxy group or the acyloxy groupinclude an acetyloxy group, a trifluoroacetyloxy group, a benzoyloxygroup and a benzylcarbonyloxy group. It may also be anN-isobutyloxycarbonylprolyloxy group or an N-benzyloxycarbonylprolyloxygroup. Here, m is an integer of 1 to 4 and n is an integer of 0 to 3,and the sum of m and n is 4.

The compound (3) may be generally selected from sodium borohydride,lithium borohydride, zinc borohydride, sodium cyano borohydride andsodium alkoxyborohydride. As an alkoxy group of sodiumalkoxyborohydride, alkoxy groups having 1 to 6 carbon atoms arepreferable, and sodium borohydride is more preferable.

The reducing agent is used in an amount in the range of preferably from1.0 to 10.0 equivalents, more preferably 1.5 to 3.5 equivalents withregard to the compound represented by the formula (1).

Examples of the phase transfer catalyst used herein include quaternaryammonium salts such as tetraethylammonium chloride, tetrabutylammoniumchloride, tetrabutylammonium bromide, tetrabutylammonium iodide,tetrabutylammonium hydrogen sulfate and trioctylmethylammonium chloride,quaternary phosphonium salts such as tetrabutylphosphonium chloride andtetrabutylphosphonium bromide, and crown ether. Among these, quaternaryammonium salts are preferable, and as the quaternary ammonium salt,trioctylmethylammonium chloride, tetrabutylammonium chloride,tetrabutylammonium bromide and tetrabutylammonium hydrogen sulfate arepreferable, with trioctylmethylammonium chloride being more preferable.When using a quaternary phosphonium salt, tetrabutylphosphonium chlorideis preferable.

The phase transfer catalyst is used in the range of preferably from 1.0to 30% by mole, more preferably from 10 to 20% by mole with regard tothe compound represented by the formula (1).

Referring to the reaction solvent, it is preferable to use a combinationof water and any of the solvents listed below. As the solvent, ethersolvents such as dialkyl ether (diethyl ether, diisopropyl ether, methylt-butyl ether, ethyl t-butyl ether, methyl n-butyl ether, ethyl n-butylether, cyclopentyl methyl ether and the like); aromatic solvents such astoluene and benzene; ester solvents such as ethyl acetate; polarsolvents such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide,dimethyl sulfoxide and alcohol; aliphatic solvents such as hexane,heptane, octane and cyclohexane; and the like may be used. Of thesenon-polar solvents are preferable, and diisopropyl ether, methyl t-butylether, cyclopentyl methyl ether, toluene, hexane, heptane, octane andcyclohexane are more preferable, and methyl t-butyl ether and heptaneare particularly preferable. In addition, a mixture of two or moresolvents may be used. In view of the reaction rate, the solubility andthe proportion of generated diastereomers of the compound (2), methylt-butyl ether and heptane are preferable. The mixing ratio of water andthe solvent is in the range of preferably from 1:8 to 1:1, morepreferably from 1:4 to 1:1. The total amount of solvent is in the rangeof preferably from 1 to 5 (v/w), more preferably from 2 to 4 (v/w) basedon the compound represented by the formula (1).

As the reaction solvent, water alone may be used, or a dilutedhydrochloric acid or an aqueous sodium hydroxide solution may also beused.

In the method of production according to the present invention, thecompound (2) maybe produced by a reaction with a reducing agent in thepresence of a phase transfer catalyst for 1 to 24 hours. Depending onthe kind of the solvent, the reaction may be completed in a few hours.

The reaction may be effected in a temperature range of from 5 to 60° C.,preferably from 10 to 50° C., more preferably from 15 to 30° C. When thecalorific value is great upon the reaction, it is desirable to effectthe reaction under cooling.

After completion of the reaction, the compound (2) is collected from thereaction mixture according to a method usually employed. For example,the compound (2) can be collected by removing inorganic substances as anaqueous layer and distilling off the solvent in the organic layer. Theobtained target compound can be further purified by distillation orchromatography according to need. The compound (2) can be prepared bythese procedures.

The configuration of the fluorine atom at the 2-position and thecarboxylic acid moiety at the 1-position of the compound (2) includestwo types: one is a configuration in which both are present on the sameside of a plane of a cyclopropane ring (cis-form) and the other is aconfiguration in which each is present on a different side of a plane ofa cyclopropane ring (trans-form). According to the method of productionof the present invention, the cis-form and the trans-form are producedin a proportion range of 87:13 to 97:3. The method of production of thepresent invention is thus excellent for producing1,2-cis-2-fluorocyclopropane-1-carboxylic acid which is a syntheticintermediate for synthetic new quinolone antibacterial agents. In themethod of production of the present invention, the content of thetrans-form is decreased compared to the content thereof before the startof the reaction, while the content of the cis-form in the reactionmixture is increased after the reaction. Accordingly, the objectivecis-forms can be advantageously obtained by the method of the presentinvention.

1,2-cis-2-Fluorocyclopropane-1-carboxylic acid can be produced byoptical resolution according to a usual method after deriving2-fluorocyclopropane-1-carboxylic acid from2-fluorocyclopropane-1-carboxylic acid ester which is a mixture ofdiastereomers obtained by the method of production according to thepresent invention.

Optical resolution can be carried out by preferential crystallization,diastereomer synthesis, an enzymatic method, chromatography or others.Specifically, for example, after hydrolyzing2-fluorocyclopropane-1-carboxylic acid ester, the hydrolyzed product(racemic form) is allowed to react with an optical resolution agent toprepare a mixture of diastereomer salts of optically active2-fluorocyclopropane-1-carboxylic acid and an optical resolution agent,and after separating desired diastereomer salts by precipitation or thelike, the separated diastereomer salts are treated with alkali. Then theobtained optically active compound is isolated.

In this regard, since cis-form and trans-form of an ester compound canbe separated by a distillation procedure, efficiency of opticalresolution can be increased by preparing an ester compound from whichtrans-forms are removed by a distillation procedure in advance and usinga carboxylic acid compound obtained by hydrolyzing the ester compound.

As the optical resolution agent, (+) and(−)-N-benzyl-α-methylbenzylamine, (+) and (−)-α-methylbenzylamine, (+)and (−)-α-ethylbenzylamine, (+) and (−)-(p-tolyl)ethylamine, (+) and(−)-phenyl-2-(p-tolyl)ethylamine, (+) and(−)-erythro-2-amino-1,2-diphenylethanol, (+) and (−)-1-(1-naphthyl)ethylamine, (+) and (−)-cis-2-(benzylamino)cyclohexane methanol, (+) and(−)-α-methyl-p-nitrobenzylamine and the like may be used andappropriately selected depending on the optical isomer of2-fluorocyclopropane-1-carboxylic acid to be obtained.

The optical resolution agent is preferably reacted in dialkyl ether, andexamples of dialkyl ether include methyl t-butyl ether, ethyl t-butylether, methyl n-butyl ether, ethyl n-butyl ether and cyclopentyl methylether. Of these, methyl t-butyl ether is preferably used.

For alkali treatment of diastereomer salt, bases like alkali metalhydroxides such as sodium hydroxide and potassium hydroxide, alkalimetal carbonates such as sodium carbonate and potassium carbonate andalkali metal hydrogen carbonates such as sodium hydrogen carbonate andpotassium hydrogen carbonate are usually used.

EXAMPLES

The present invention is described by means of Examples, which is notconstructed as limiting the present invention.

Example 1 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)1

To a solution heated to 40° C. obtained by dissolving t-butyl1-chloro-2-fluorocyclopropane-1-carboxylate (tertiary butyl ester;cis/trans=62/38; in this specification, regardless of the presence orabsence of a halogen atom at the 1-position, a compound in which afluorine atom and a carboxylic acid ester moiety are present on the sameside of a plane of a cyclopropane ring is referred to as cis-form; 0.97g, 5.0 mmoles) and tetrabutylammonium bromide (161 mg, 10% by mole) inmethyl t-butyl ether (1.94 mL), an aqueous solution of sodiumborohydride (concentration: 1 g/2.6 mL, 1.45 mL) was gradually addedwith stirring using a stirring blade. After the addition, the mixturewas stirred using a stirring blade at 40° C. for 20 hours, and thenwater was added to the reaction mixture. Diisopropyl ether was added tothe mixture to conduct extraction (30 mL×3) to give a diisopropyl ethersolution containing 424 mg of the title compound (2a) (quantitation byhigh performance liquid chromatography, yield 53%). HPLC analysisconditions: column: MERCK Chromorith Performance RP-18 100-4.6 mm,mobile phase: pH 4.2 phosphate buffer/acetonitrile=70/30, flow rate: 1.0mL/min, detection wavelength: 220 nm. Further, gas chromatographyanalysis was conducted and cis/trans=95/5 was found [analysisconditions: detector: FID, column: GLscience, NEUTRA BOND-5, 30 m×0.25mm, temperature of vaporization chamber: 250° C., detector temperature:250° C, carrier gas: nitrogen (80 kPa), hydrogen (60 kPa), air (50kPa)].

Example 2 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)2

The same procedures as in Example 1 were conducted except that hexanewas used as a reaction solvent instead of methyl t-butyl ether, and themixture was stirred at 40° C. for 6 hours. Subsequently, the sametreatment as in Example 1 was conducted, and a diisopropyl ethersolution containing a compound (2a) was analyzed by HPLC and a yield of59% was found. GC analysis was conducted and cis/trans=96/4 was found.

Example 3 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)3

t-Butyl 1-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans=62/38, 3g, 15.4 mmoles) and trioctylmethylammonium chloride (1.25 g, 20% bymole) were dissolved in heptane (6 mL), and sodium borohydride (1.75 g,46.2 mmoles) was added to the solution at room temperature. After theaddition, water (4.5 mL) was added to the solution and the mixture wasstirred for 3 hours at the same temperature. After adding water to thereaction solution, methyl t-butyl ether was added to conduct extraction(50 mL×3) to give a methyl t-butyl ether solution containing 2.22 g ofthe title compound (2a) (quantitation by high performance liquidchromatography, yield 89%). GC analysis was conducted andcis/trans=90/10 was found.

Example 4 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)4

t-Butyl 1-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans=62/38, 1g, 5.1 mmoles) and trioctylmethylammonium chloride (415.3 mg, 20% bymole) were dissolved in heptane (2 mL), and sodium borohydride (583.1mg, 15.4 mmoles) was added to the solution at 40° C. After the addition,a 0.1 N aqueous sodium hydroxide solution (1.5 mL) was added to thesolution and the mixture was stirred for 7 hours at the sametemperature. After adding water to the reaction mixture, methyl t-butylether was added to conduct extraction (30 mL×3) to give a methyl t-butylether solution containing 663.7 mg of the title compound (2a)(quantitation by high performance liquid chromatography, yield 77%). GCanalysis was conducted and cis/trans=91/9 was found.

Example 5 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)5

In the same manner as in Example 4 except that the mixture was stirredfor 24 hours after adding a 0.1 N aqueous sodium hydroxide solution (1.5mL), a methyl t-butyl ether solution containing 543.2 mg of the titlecompound (2a) was obtained (quantitation by high performance liquidchromatography, yield 66%). GC analysis was conducted andcis/trans=88/12 was found.

Example 6 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)6

t-Butyl 1-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans=62/38, 1g, 5.1 mmoles) and trioctylmethylammonium chloride (415.3 mg, 20% bymole) were dissolved in toluene (2 mL), and sodium borohydride (583.1mg, 15.4 mmoles) was added to the solution at 40° C. After the addition,water (1.5 mL) was added to the solution and the mixture was stirred for24 hours at the same temperature. After adding water to the reactionmixture, methyl t-butyl ether was added to conduct extraction (30 mL×3)to give a methyl t-butyl ether solution containing 477.4 mg of the titlecompound (2a) (quantitation by high performance liquid chromatography,yield 58%). GC analysis was conducted and cis/trans=89/11 was found.

Example 7 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)7

t-Butyl 1-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans=62/38, 1g, 5.1 mmoles) and trioctylmethylammonium chloride (415.3 mg, 20% bymole) were dissolved in cyclopentyl methyl ether (2 mL), and sodiumborohydride. (583.1 mg, 15.4 mmoles) was added to the solution at 40° C.After the addition, water (1.5 mL) was added to the solution and themixture was stirred for 24 hours at the same temperature. After addingwater to the reaction mixture, methyl t-butyl ether was added to conductextraction (30 mL×3) to give a methyl t-butyl ether solution containing535.0 mg of the title compound (2a) (quantitation by high performanceliquid chromatography, yield 65%). GC analysis was conducted andcis/trans=89/11 was found.

Example 8 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)8

In the same manner as in Example 7 except that the solvent was changedto octane, a methyl t-butyl ether solution containing 609.1 mg of thetitle compound (2a) was obtained (quantitation by high performanceliquid chromatography, yield 74%). GC analysis was conducted andcis/trans=89/11 was found.

Example 9 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)9

In the same manner as in Example 7 except that the solvent was changedto hexane, a methyl t-butyl ether solution containing 592.6 mg of thetitle compound (2a) was obtained (quantitation by high performanceliquid chromatography, yield 72%). GC analysis was conducted andcis/trans=90/10 was found.

Example 10 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)10

t-Butyl 1-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans=62/38, 1g, 5.1 mmoles) and tetrabutylammonium chloride (285.6 mg, 20% by mole)were dissolved in methyl t-butyl ether (3 mL), and sodium borohydride(583.1 mg, 15.4 mmoles) was added to the solution at 40° C. After theaddition, 0.02 N hydrochloric acid (1.5 mL) was added to the solutionand the mixture was stirred for 22 hours at the same temperature. Afteradding water to the reaction mixture, methyl t-butyl ether was added toconduct extraction (30 mL×3) to give a methyl t-butyl ether solutioncontaining 395.0 mg of the title compound (2a) (quantitation by highperformance liquid chromatography, yield 48%). GC analysis was conductedand cis/trans=92/8 was found.

Example 11 Production of t-butyl 2-fluorocyclopropane-1-carboxylate (2a)11

t-Butyl 1-chloro-2-fluorocyclopropane-1-carboxylate (cis/trans=62/38, 1g, 5.1 mmoles) and tetrabutylammonium hydrogen sulfate (349.0 mg, 20% bymole) were dissolved in methyl t-butyl ether (3 mL), and sodiumborohydride (583.1 mg, 15.4 mmoles) was added to the solution at 40° C.After the addition, 0.02 N hydrochloric acid (1.5 mL) was added to thesolution and the mixture was stirred for 24 hours at the sametemperature. After adding water to the reaction mixture, methyl t-butylether was added to conduct extraction (30 mL×3) to give a methyl t-butylether solution containing 395.0 mg of the title compound (2a)(quantitation by high performance liquid chromatography, yield 58%). GCanalysis was conducted and cis/trans=93/7 was found.

Reference Example 1 Production of (1S,2S)-2-fluorocyclopropane-1-carboxylic acid

A 5 N aqueous sodium hydroxide solution (6.8 mL) was added to an ethanolsolution (6.8 mL) of compound (2a) obtained in the Examples to conduct areaction at 50° C. for 12 hours. After the completion of the reaction,the mixture was cooled to room temperature and ethanol was removed underreduced pressure. To the obtained residue was added 1 N hydrochloricacid under cooling with ice so that the pH became pH 2 or lower, andextraction by methyl t-butyl ether was conducted (15 mL×2). The organiclayer was dried over magnesium sulfate and methyl t-butyl ether wasremoved under reduced pressure to give a racemic form of2-fluorocyclopropane-1-carboxylic acid. The racemic form was dissolvedin methyl t-butyl ether (30 mL) and with stirring the mixture at roomtemperature, (R)-(+)-N-benzyl-α-methylbenzylamine (1.0 equivalent) wasadded thereto dropwise. The precipitated diastereomer salt of1,2-cis-2-fluorocyclopropane-1-carboxylic acid and(R)-(+)-N-benzyl-α-methylbenzylamine was recrystallized in isopropylether (45 mL) (yield: 1.51 g, optical purity: 99% e.e.). Subsequently, a2 N aqueous sodium hydroxide solution (4.7 mL) was added to the obtaineddiastereomer salt, and the mixture was washed with chloroform (10 mL×2),and the aqueous layer was neutralized with 6 N hydrochloric acid (5mL).After the neutralization, extraction by ethyl acetate was conducted (10mL×3), and the organic layer was dried over magnesium sulfate and ethylacetate was removed under reduced pressure to give the title compound(yield: 478.3 mg, optical purity: 99% e.e.).

INDUSTRIAL APPLICABILITY

By using the method of production of the present invention, the reactiontime of a dehalogenation reaction of1-halogeno-2-fluorocyclopropane-1-carboxylic acid ester can besignificantly shortened as compared to the reaction time in previousmethods. In particular, even in the case of using an apparatus forindustrial production, the reaction can be completed in a shorter time.Furthermore, because dimethyl sulfoxide is not used as a reactionsolvent in the method of production according to the present invention,the problem of generation of dimethyl sulfide has also been solved.Accordingly, the method of production of the present invention isindustrially applicable as a method of producing a synthetic rawmaterial for synthetic new quinolone antibacterial agents.

1. A method of producing 2-fluorocyclopropane-1-carboxylic acid ester,which comprises allowing a compound represented by the following formula(1):

wherein X represents a chlorine atom, a bromine atom or an iodine atom;and R¹ represents an alkyl group having 1 to 8 carbon atoms, an arylgroup having 6 to 12 carbon atoms, an alkenyl group having 2 to 8 carbonatoms, or an aralkyl group with an aryl group having 6 to 12 carbonatoms and an alkylene group having 1 to 6 carbon atoms; to react with areducing agent in the presence of a phase transfer catalyst and areaction solvent excluding dimethyl sulfoxide.
 2. The method accordingto claim 1, wherein X in the formula (1) is a chlorine atom.
 3. Themethod according to claim 1 wherein R¹ in the formula (1) is an alkylgroup having 1 to 8 carbon atoms.
 4. The method according to claim 3,wherein the alkyl group having 1 to 8 carbon atoms is a t-butyl group.5. The method according to claim 1, wherein the phase transfer catalystis a quaternary ammonium salt.
 6. The method according to claim 5,wherein the quaternary ammonium salt is tetrabutylammonium bromide. 7.The method according to claim 5, wherein the quaternary ammonium salt istetrabutylammonium chloride.
 8. The method according to claim 5, whereinthe quaternary ammonium salt is tetrabutylammonium hydrogen sulfate. 9.The method according to claim 5, wherein the quaternary ammonium salt istrioctylmethylammonium chloride.
 10. The method according to claim 1,wherein the reducing agent is sodium borohydride.
 11. The methodaccording to claim 1, wherein the reducing agent represented by thefollowing formula (3)MBH_(m)R² _(n)  (3) wherein M represents an alkali metal atom; R²represents a hydrogen atom, a cyano group, an alkoxy group or an acyloxygroup, which alkoxy group or acyloxy group may be further substituted bya halogen atom; m is an integer of 1 to 4; n is an integer of 0 to 3;and the sum of m and n is
 4. 12. The method according to claim 1,wherein the reaction solvent is water alone, a diluted hydrochloric acidor an aqueous sodium hydroxide solution, or a combination of water andat least one solvent selected from the group consisting of dialkylethers, toluene, benzene; ethyl acetate, tetrahydrofuran, acetonitrile,N,N-dimethylformamide, alcohol, hexane, heptane, octane and cyclohexane.13. The method according to claim 12, wherein the reaction solvent is acombination of water and a solvent selected from the group consisting ofdiisopropyl ether, methyl t-butyl ether, cyclopentyl methyl ether,toluene, hexane, heptane, octane and cyclohexane.
 14. The methodaccording to claim 13, wherein the reaction solvent is a combination ofwater, methyl t-butyl ether and heptane.
 15. The method according toclaim 13, wherein the mixing ratio of water and the solvent is in therange of from 1:8 to 1:1.
 16. The method according to claim 15, whereinthe mixing ratio of water and the solvent is in the range of from 1:4 to1:1.
 17. The method according to claim 1, wherein the2-fluorocyclopropane-1-carboxylic acid ester is produced as a mixture ofcis and trans forms, in a ratio range of cis:trans of 87:13 to 97:3. 18.The method according to claim 17, wherein said compound of formula (1)is a mixture of cis and trans forms, and the content of trans form insaid mixture of 2-fluorocyclopropane-1-carboxylic acid ester is lessthan the trans form content of said compound of formula (1), and thecontent of cis form in said mixture of 2-fluorocyclopropane-1-carboxylicacid ester is greater than the cis form content of said compound offormula (1).
 19. The method according to claim 1, additionallycomprising deriving 2-fluorocyclopropane-1-carboxylic acid from the2-fluorocyclopropane-1-carboxylic acid ester.
 20. The method accordingto claim 19, additionally comprising optically resolving the2-fluorocyclopropane-1-carboxylic acid to produce1,2-cis-2-fluorocyclopropane-1-carboxylic acid.